Alkoxy-trifluoromethylphenalkyl-
amines

ABSTRACT

ALKOXY-TRIFLUOROMETHYLPHENALKYL AMINES USEFUL STO REDUCED NAUSEA AND TO DEPRESS APPETITE .! AND THE PROCESS OF REDUCING APPETITE BY THE ADMINISSTRATION OF A LOWERALKOXY-SUBSTITUTED TRIFLUOROMETHYLPHENALKYL SECONDARY AMINE.

United States Patent ,8-ALKOXY-TRIFLUOROMETHYLPHENALKYL- AMINES John A.Faust, Solvang, Calif., and Melvill Sahyun, 102 E. Pueblo St., SantaBarbara, Calitl; said Faust assignor to Said Melville Sahyun, doingbusiness as Sahyun Laboratories, Santa Barbara, Calif.

No Drawing. Original No. 3,459,803, dated Aug. 5, 1969,

Ser. No. 666,457, Sept. 8, 1967, which is a continuationin-part of Ser.No. 467,759, June 28, 1965. Application for reissue July 28, 1970, Ser.No. 59,042

Int. Cl. C07c 93/02 US. Cl. 260570.6 7 Claims Matter enclosed in heavybrackets appears in the original patent but forms no part of thisreissue specification; matter printed in italics indicates the additionsmade by reissue.

ABSTRACT OF THE DISCLOSURE Alkoxy-trifluoromethylphenalkyl amines usefulto reduce nausea and to depress appetite [.J and the process of reducingappetite by the administration of a loweralkoxy-substitutedtrifluoromethylphenalkyl secondary amme.

This invention relates to novel secondary amines, more particularly tolower-alkoxy-substituted trifluoromethylphenalkyl secondary amines.

This application is a continuation-in-part of application S.N. 467,759,filed June 28, 1965 and now abandoned. The composition aspect of thisinvention resides in the concept of loWer-alkoxy-substitutedtri-fluoromethylphenalkyl secondary amines.

The process of use aspect of this invention resides in the concept ofadministering a lower-alkoxy-substituted trifiuoromethylphenalkylsecondary amine in a pharmaceutically acceptable form to mammaliananimals to reduce nausea.

Another process of use aspect of this invention resides in the conceptof administering a lower-alkoxy-substituted trifluoromethylphenalkylsecondary amine in a pharmaceutically acceptable form to mammaliananimals to reduce appetite.

The phenalkylamines of this invention can be represented by the formulawherein R is hydroxyethylene or hydrocarbon containing l-8 carbon atoms,preferably lower-al-kyl, and A is a 1-3 carbon atom alkylene bridge,containing a total of l-8 carbon atoms, joining the lower-alkoxygroup-bearing carbon atom and the amine nitrogen atom, e.g., methylene,ethylene and trimethylene, any of whose carbon atoms can bear one ormore alkyl groups so as to contain up to a total of 8 carbon atoms,preferably methylene with or without a methyl group. Especiallypreferred are each of the above wihose CF group is in the meta-position.

As used herein, the term hydrocarbon" includes alkyl, e.g., methyl,ethyl, octyl, alkenyl, e.g. allyl, alkynyl, aryl, e.g., phenyl, alkaryl,e.g., tolyl, aralkyl, e.g., benzyl, phenethyl, cycloalkyl, e.g.,cyclopropyl, cyclopentyl, cyclohexyl, cyclohexylmethyl and cycloalkenyl,e.g., cyclohcx- Re. 27,551 Reissued Jan. 16, 1973 ice enyl. Preferredare the saturated hydrocarbon of e.g., alkyl, cycloalkyl,alkylcycloalkyl and cycloalkylalkyl, especially cycloalkyl and alkyl.

As used herein the terms lower-alkyl" and loweralkoxy referrespectively, to alkyl and alkoxy groups containing from one to eightcarbon atoms, preferably less than five carbon atoms, which can bestraight-chain or branched. Representative alkyl radicals are methyl,ethyl, propyl, isopropyl, n-butyl and sec-butyl, amyl, isoamyl, hexyl,heptyl and octyl. Representative lower-alkoxy radicals are methoxy,ethoxy, propoxy, isopropoxy, n-butoxy, and sec-butoxy, amyloxy andoctyloxy.

Racemic mixtures are obtained as the carbon atom which bears the ethersubstituent and which is attached to the benzene ring is asymmetric.Also, when a carbon atom in the methylene chain is asymmetric, a furtherracemate mixture is possible. Racemate pairs can be separated byfractional crystallization of an acid addition salt and each d and lisomer can be separated from the racemate in the conventional manner.

The compounds of this invention comprise the acid addition salts. Whenthe tangible embodiments of the invention are employed for theirpharmacological eiiect, they ordinarily will be used in the form oftheir nontoxic acid addition salts, i.e., pharmacentically acceptablesalts. However, any acid addition comes within the scope of thisinvention as they are all useful, e.g., for purifying the free base orfor separating racemate mixtures.

Suitable non-toxic, i.e., pharmaceutically acceptable, acid additionsalts are those formed from mineral acids, e.g., hydrochloric acid,hydrobromic acid, hydroiodic acid, nitric acid phosphoric acid andsulfuric acid, and organic acids, e.g., acetic acid, citric acid,tartaric acid, lactic acid, and the like, which provide thehydrochloride, hydrobromide, hydroiodide, nitrate, phosphate or acidphosphate, sulfate or bisulfate, acetate, citrate or acid citrate,tartrate or bitartrate, and the lactate salts, respectively.

Equivalents of the compounds of this invention are those of the aboveformula bearing additional simple substituents on the benzene ring ofthe molecule, e.g., one, two or more of lower-alkyl, aryl, alkaryl,halo, including, chloro and bromo, trifluoromethyl, hydroxy, nitro,etc., in the 2,4,5, or 6-position.

Preferred of the compounds of this invention are those wherein theN-lower-alkyl group is methyl or ethyl, the lower-alkoxy group ismethoxy or ethoxy, and the methylene bridge contains one or at most twocarbon atoms, i.e., the alpha-unsubstituted and alpha-methyl-phenethylcompounds, and those having combinations of these preferred groups,e.g.,

N,u-di-methyl-beta-methoxy-m-trifluoromethylphenethyl- N- r gt l iyl-beta-methoxy-m-trifluoromethylphenethyl- N- r r l e tha-beta-ethoxy-m-trifiuoromethylphenethylarnine,N-ethyl-beta-methoxy-m-trifiuoromethylphenethylamine, Niiiiyl-beta-ethoXy-m-trifluoromethylphenethylamine.

The following is the manner and process of making and using theinvention and the best mode contemplated of carrying out the invention.

The compounds of this invention can be prepared by first converting atrifluoromethyl substituted phenyl bromide to the corresponding Grignardreagent.

The magnesium Grignard reagent is then reacted with a lower-alkyla,w-dihalo-lower-alkyl ether to form a trifluoromethylphenal'kyl halidebearing a lower-alkoxy group on the carbon atom alpha to the phenylring. Displacement of the halogen atom by reaction with a primary amineproduces the compounds of this invention.

These reactions can be illustrated by the following formulae:

O-lower-alkyl A and R having the value given above and X is Cl or Br.The compounds of this invention possess anti-emetic, anti-tussive andanorexic activities. In addition, they exhibit some N5 eifects,manifested primarily as depressant, e.g., sedative activities, in mostspecies usually at doses higher than that required to obtain anti-emeticor anorexic activity. Mydriasis is also produced at high dosage levels.They are nicotine antagonists and protect at low oral doses againstotherwise fatal doses of nicotine. The combination of anti-emetic andanti-tussive activities is unusual in phenethylarnines, whether thefi-methylene carbon atom is unsubstituted or substituted with hydroxy oralkoxy, Similarly, phenethylamines known to possess anti-emeticactivity, e.g., the amphetamines, also undesirably produce CNSstimulation, e.g., pressor, efiects.

The compounds of this invention can be administered orally,subcutaneously, intravenously, intraperitoneally, etc., in the usualpharmaceutical forms, e.g., admixed with pharmaceutical excipients inthe form appropriate, e.g., tablets, capsules, suppositories, in liquidemulsions, solutions, suspensions, etc. Their intravenous andintramuscular antiemetic activity is particularly valuable because ofthe difiiculty in orally administering drugs in cases of extreme nausea.The selected compound generally should be present in a concentrationwhich will provide at least about 1 mg. per unit dosage, i.e., pertablet, capsule, teaspoonful, etc. The usual I.M. oral dose is about 0.1to 2.0 mg./kg. or more. Up to about 5 mg./kg About or more times thisdosage can be administered to laboratory test animals for test purposes.Efl'ective LP. and oral dosages are about 1.510 times these amounts.

The followingpreparations and examples are illustrative of the compoundsof this invention and of the processes by which 'they can be prepared.Temperatures are given in degrees centigrade.

PREPARATION 1 Beta-mothoxy-3-trifluoromethyl-phenethyl bromide To astirred solution of the Grignard reagent prepared from 12 4 grams (0.5mole) of 3-bromo-alpha, alpha, alpha-trifluorotoluene and 14 grams (0.57mole) of magnesium in 500 milliliters of anhydrous ether was added anether solution of 109 grams (0.5 mole) of alpha, betad'ibromoethylmethyl ether. The homogeneous reaction mixture was allowed to remainovernight at 25 degrees and was then refluxed for 6 hours. The mixturewas poured into iced dilute hydrochloric acid. The ether layer wasseparated, washed, dried and distilled. The yield ofbeta-methoxy-3-trifluoromethyl-phenethyl bromide was 125 grams (80percent), B.P. 82-87 C./ 1.7 mm.; 119- 120 C./ 20 mm.

PREPARATION 2 Beta-ethoxy-3-triiiuoromethyl-phenethyl bromide Thereaction of 0.3 mole of alpha, beta-dibromoethyl ethyl ether with 0.3mole of 3-trifluoromethyl-phenyl magnesium bromide according to themethod of Preparation 1 gave on distillation 60 grams (67 percent) ofbetaethoxy-3-trifluoromethyl-phenethyl bromide, B.P. 88-90 C./0.2 mm.

In the same manner, beta-n-butoxy-3-trifiuoromethylphenethyl bromide isprepared from alpha, beta-dibromoethyl n-butyl ether.

Following the procedure of Preparation 1, betamethoxy 4trifluoromethyl-phenethylbromide and other beta-lower alkoxy4-trifluoromethylphenethyl bromides are prepared by the reaction of 4trifluoromethylphenethyl magnesium bromide with alpha, beta-dibromoethylethyl ether and other alpha, beta-dibromoethyl lower-alkyl ethers. Thecorresponding beta-methoxy 2 trifiuoromethylphenethyl bromide and otherbeta-lower-alkoxy Z-trifluoromethylphenethyl bromides are similarlyprepared using Z-trifluoromethylphenyl magnesium bromide. Thealpha-alkyl-beta-lower alkoxy-2-, 3- and 4-trifluoromethylphenethylbromides are prepared by employing the appropriatealpha-beta-dihalo-loweralkyl lower-alkyl ether.

Example l.N-methyl-fi-methoxy-B- 3-tril1uoromethyl) phenethylaminehydrochloride A mixture of 40 g. (0.14 mole) ofp-rnethoxy-3-trifluoromethylphenethyl bromide, 40 g. (1.3 mole) ofmonomethylamine and 400 ml. of isopropyl alcohol, contained in apressure vessel, was heated at 60-65" for 24 hours. The excessmethylamine and alcohol were removed by distillation, and the residuewas partitioned between dilute hydrochloric acid and ether. The aqueoussolution was made alkaline with sodium hydroxide and the liberated oilybase was extracted with ether. Distillation of the dried ether solutionyielded 18.6 g. (57 percent) of N-methyl-fl-methoxy-B-G trifiuoromethyl)phenethylamine, B.P. 113117 (21 mm.).

Analysis-Calculated for C H F NO: N, 6:00 Neut. Equiv., 233. Found: N,5.50; Neut. Equiv., 240.

The hydrochloride, prepared in ether and recrystallized from a mixtureof isopropyl alcohol and ether, melted at -196".

Analysis.Calculated for C H F NO-HCl: N, 5.19; Cl, 13.14. Found: N,5.00;C1", 13.56.

'Example 2.N-methyl-B-methoxy- -(2-trifluoromethyl) phenethylaminehydrochloride (a) fi-Methoxy B (Z-trifiuoromethyl)phenethyl bromide.-Tothe Grignard reagent, prepared from 22.5 g. (0.1 mole) of commercialo-bromobenzotrifluoride and 2.4 g. (0.1 g. at.) of magnesium in ether,there was added, dropwise at 25 an ether solution of 21. 8 g. (0.1 mole)of u,fl-dibromoethyl-methyl ether. (J. Am. Chem. Soc. 52, 651 (1930);J.C.S. 1942, 520.) The reaction caused the ether to reflux, andrefluxing was continued for one hour after the addition. The cooledsolution was poured over iced hydrochloric acid and the ether layer wasseparated, washed with water, dried and distilled to yield 15.6 g. (55percent) of fl-methoxy-fl-(Z-trifluoromethyl) phenethyl bromide, B.P.71-75 (0.5 mm.).

(b) N-methyl-fl-methoxy p (Z-trifluoromethyDphenethylaminehydrochloride.--A solution of 11.8 g. (0.042 mole) offl-methoxy-p-(Z-trifluoromethyl)phenethyl bromide in 75 ml. of isopropylalcohol containing 16- g. (0.5 mole) of methylamine was heated, in apressure bottle, at 65 for 44 hours. The cooled solution was distilledto remove the excess methylamine and isopropyl alcohol and the residuewas partitioned between dilute hydrochloric acid and ether. The aqueoussolution was made alkaline and the liberated base was extracted withether and distilled. Yield, 3.3 g. (34 percent) of N-methyl-fi-methoxy-B-(2fifluoromethyl)phenethylamine, B.P. 113-115 (22 mm.

Analysis-Calculated for C I-I F NO: N, 6.01; Neut. Equiv., 233. Found:N, 5.68; Neut. Equiv., 235.

The hydrochloride, prepared in ether with ethereal hy- 5 drogenchloride, melted at 257258 after recrystallization from methanol-ether.

Analysis-Calculated for C H F NO-HClz N, 5.19; (31-, 13.15. Found: N,4.80; (31-, 13.40.

' Example 3.-N-methyl-;9-methoxy-fi-(4-trifluoromethyl) phenethylaminehydrochloride (a) B-Methoxy-fl-(4-trifluorornethyl)phenyl bromide.- Thiscompound was prepared in the same manner as the corresponding2-trifiuoromethyl compound as described in Example 2a. From 0.1 mole ofp-bromobenzotriflueride there was obtained 16.8 g. (72 percent) offl-methoxyfl-(4-trifluoromethyl)phenyl bromide, B.P. 7l-75 .5 mm.).

(b) N-methyl-p-methoxy B (4-trifiuoromethyl)phenethylaminehydrochloride.A heterogenous mixture of 1 6.8 g. (0.06 mole) of thebromo compound of Example 2a and 92 g. (1.2 mmole) of 40 percent aqueousmethylamine was heated at 50-5S in a pressure bottle, for 64 hours. Theexcess methylamine was removed by distillation, and the residue waspartitioned between dilute hydrochloric acid and ether. The aqueoussolution was made alkaline, and the liberated base was extracted withether and distilled. Yield: 3.4 g. (24 percent) ofN-methyl-fi-methoxy-B-(4 trifluoromethyl)phenethylamine, B.P. 120-122(20 mm.).

The hydrochloride, prepared in ether with ethereal hydrogen chloride,melted at 233-234 after recrystallization from a mixture of ethanol andether.

6 (c) N-methyl-w-methoxyy-(3 trifluoromethylphenyl) propylaminehydrochloride.An autoclave was charged with 175 m1. of isopropyl alcoholcontaining 31 g. (1 mole) of methylamine and 17.3 g. (0.068 mole) of theabove chloro-ether. The temperature of the mixture was maintained at95-100 for 14 hours, after which the solution was distilled to removethe excess methylamine and the solvent. The residue was partitionedbetween dilute hydrochloric acid and ether, and the aqueous solution wasrendered alkaline. The liberated base was isolated by ether extractionand distilled. Yield: 9 g. (54 percent) of N-methyl-y-methoxy-y-( 3tri-fluoromethylphenyl)propylamine, B.P. 126128 (20 mm.).

Analysis.-Calculated for C H F NOz N, 5.67; Neut.

15 Equiv., 247. Found: N, 5.32; Neut. Equiv., 238.

The hydrochloride, prepared in ether with hydrogen chloride, melted atIll-112 after recrystallization from a mixture of ethanol and ether.

Analysis.Calculated for c H F NO-Hcl: N, 4.94;

01-, 12.45. Found: N, 4.81; 01-, 12.71.

Following the procedure of Example 1, the following compounds wereprepared by substituting the appropriate amine for the methylamine inthe alkylation reaction OR CHANHR CF; v

B P. (base) CF; R" A R (mm) M.P. (-HCl) in H CH, 01H; 122-4/20 189-199 mH CH1 04H, 145-7/20 138-130 In H CH: omens), 1 155-157 111 1%! CH:CHgCH=CH a 145-147 In H CH2 CH|CHIOH 152-153 111 CH: oyclohexyl 106-9/0.25 I 140-141 in CH: benzyl 135-7/0. 8 165-167 In H CH: phenethyl 170-171m H CH CH; 142-144d In H CH: CHxCHjOH 1345.0/0.2

m H CH: CH; 134-8 20 1223-129 111 H CH(CH;) CH; 119-20 23 155-156 In HOH: cyclopentyl 6 144-145 111 H CH1 C(CHs)s 125-28/26 235-235 p H OH:cyclopentyl 1 188-189 D H OH; cyclohexyl I 224-225 In P'CHZO CH: CH;110-12/0.55 183-184 In -CH=0 0H, 011mm). 187-189 5 acme 0H, H, 1 146-1415 2-GHIO 0H1 011(0119, 115-17 0.5 I 200-201 I Reeryst. tsopropylalcohol-ether.

1 Recryst. acetone-eth I Recryst. acetone. Recryst. ethanol-ether. iRecryst. benzene-pet. ether.

Example 4.N-methyl-'y-methoxy-(B-trifluoromethylphenyl)propylaminehydrochloride (a) 01,7 dichloro-p-propyl methyl ether.-Hydrogen chloridewas passed through a stirred mixture of 23 g. (0.41 mole) of acroleinand 13.1 g. (0.41 mole) of methanol at 0 until 32 g. had been absorbed.After an additional 20 minutes the layers were separated and the lowerlayer was dried over calcium chloride and distilled. Yield: 38 g. (64percent) of u,'y-dichloro-p-propyl methyl ether, B.P. 48-51 (16 mm.).Reported: B.P. (12 mm.); C.A. 18, 815.

(b) 'y-methoxyy- (3-trifluoromethyl)phenylpropyl chloride.-To thestirred Grignard reagent, prepared from 27 g. (0.12 mole) ofm-bromobenzotrifluoride and 2.9 g. (0.12 g. at.) of magnesium in ether,there was added dropwise an ether solution of the above dichlorocompound. Stirring and refluxing were continued for one hour after theaddition, after which the mixture was poured over iced hydrochloricacid. The ether layer was separated, dried and fractionally distilled toyield 17.3 g. (57 percent( of 'y-methoxy 'y(3-trifiuoromethyl)phenylpropyl chloride, B.P. 82-85" (0.5 mm.).

A related invention are the primary amines otherwise corresponding tothe secondary amines described herein, i.e., those represented byFormula I wherein R is hydrogen. These compounds also possesspharmacological activity, including CNS depressant activity. They arealso useful as intermediates in the production of the correspondingsecondary amines of this invention by alkylation with an appropriatehydrocarbon halide or with ethylene oxide. The following example isrepresentative of the manner of producing these primary amines by thereaction of the corresponding lower-alkoxy-trifluoromethylphenylalkylhalide with ammonia.

fl-methoxy-flm-trifluoromethyl phenethylamine hydrochloride Twenty-twograms (0.078 mole) of B-methoxy-fl-(mtrifluoromethyl)phenethyl bromidewas combined with 400 ml. of methanol which had been saturated withammonia at 10. The solution, contained in an autoclave, was heated to-90 for 5 hours and cooled. The alcohol was removed by distillation andthe residue was partitioned between dilute sodium hydroxide and ether.The ether solution was washed, dried and distilled to yield 13.2 g. (77percent) of B-methoxy-fi-(m-trifluoromethyl) phenethylamine; B.P. -118(22 mm.). The hydro- :hloride, prepared in ether and recrystallized fromisopropyl alcohol-ether, melted at 168-169.

Analysis.Calculated for C H F NO-HCl: 'N, 5.48; 31, 13.88. Found: N,5.46; CI", 13.94.

What is claimed is: 1. A compound of the formula O-lower-alk yl whereinA is a divalent alkylene group containing from one to eight carbon atomsand forming a one to three :arbon atom bridge and R is a member of thegroup consisting of alkyl and cycloalkyl containing up to eight :arbonatoms [1], or a pharmaceutically acceptable acid Iddition salt thereof.

2. A compound of claim 1 wherein the -.CF group is meta.

3. A compound of the formula O-lower-alkyl wherein A is a divalentalkylene group containing from one to two carbon atoms and forming amethylene bridge.

4. A compound of the formula -loWer-alkyl @hHGENHJower-hk i 5.N-lower-alkyl-fi-methoxy m trifluoromethylphen- :thylamine 6.N-methyl-B-methoxy m trifluoromethylphenethylamine.

A compound of the formula O-lower-alkyl H-A'NH| wherein A is a divalentalkylene group containing from one to two carbon atoms and forming amethylene bridge[.], or a pharmaceutically acceptable acid addition saltthereof References Cited The following references, cited by theExaminer, are of record in the patented file of this patent or theoriginal patent.

UNITED STATES PATENTS 3,281,468 10/1966 Mills 260-570.6 3,079,403-2/1963 Weinstock 260-349 3,151,124 9/1964 Huebner 260-326.5 3,226,44012/1965 Sahyun et al. 260-5706 al.: Jour. Org. Chem, vol. 13, page 413ROBERT V. HINES, Primary Examiner US. Cl. X.R.

260-501.l7, 611 A, 614 R, 665 G; 424-330

